Project Summary The goal of this project is to develop a completely non-invasive, precise and durable treatment option for low back pain, which is estimated to cost $30 billion in direct health care expenditures annually. Chronic LBP is often a diagnostic and management challenge due to multiple potential pain sources with both biomechanical and inflammatory mechanisms. The failure of systemic analgesic drugs, such as opioids, is often due to their off-target toxicity, development of tolerance, and abuse potential. Interventional pain procedures provide target specificity but lack long-term efficacy and are associated with procedural risks. Understanding the supratentorial effects of such treatments may be an important part of developing effective treatment modalities. Focused ultrasound (FUS) is a lower risk, completely non-invasive modality that enables the delivery of spatially-confined acoustic energy to a small tissue region (dorsal root ganglion [DRG]) under magnetic resonance (MR) imaging guidance to treat axial low back pain by neuromodulation. The central goal of this study is to demonstrate neuromodulation of the DRG with FUS to decrease nerve conduction, which can be used to attenuate pain sensation. In the first Aim, we will establish electrophysiologic normative data for detecting changes in pain in neuritis models and normals measured by EEG and somatosensory evoked potentials. In the second Aim, we will demonstrate FUS neuromodulation of the DRG in pigs by (a) exploring FUS sonication parameters that results in DRG neuromodulation as assessed by SEPs during nerve stimulation and (b) evaluating the safety and efficacy of non-invasive FUS neuromodulation in neuritis pig model and controls by performing longitudinal unique behavioral assessments, which specifically test behaviors indicative of supraspinal pain sensation. In the third Aim, we will design and construct an LBP-specific MRgFUS device for rapid translation to patients with back pain by fully characterizing FUS sonications for DRG neuromodulation using regulatory standards, constructing an MRI radiofrequency coil and transducer mount to allow targeting of the DRG in humans, and evaluating the prototype for image and sonication quality. This exploratory study will demonstrate 1) using FUS on the DRG to interrupt and modulate nerve conduction, 2) using somatosensory evoked potentials to monitor brain changes and unique behavioral assessments in a pig model after modulating the effect of pain stimuli, 3) the safety of FUS DRG neuromodulation, and 4) a prototype for human use. Importantly, the low risk associated with FUS neuromodulation, compared to invasive procedures, will result in rapid clinical translation. We propose that FUS is a noninvasive modality to treat chronic low back pain with neuromodulation and has the potential to replace current invasive or systemically detrimental treatment modalities. By demonstrating that neuromodulation with FUS can alter pain perception with cortical monitoring and with behavioral assessments, with the ultimate goal of developing a completely non-invasive system to treat low back pain and adjust the treatment in real-time depending on the cortical response. The lower risk associated with neuromodulation, compared to more invasive procedures, will result in fast translation to humans.